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Fibroblast growth factor 9 (FGF9)-pituitary homeobox 2 (PITX2) pathway mediates transforming growth factor ? (TGF?) signaling to regulate cell proliferation in palatal mesenchyme during mouse palatogenesis.

ABSTRACT: Cleft palate represents one of the most common congenital birth defects. Transforming growth factor ? (TGF?) signaling plays crucial functions in regulating craniofacial development, and loss of TGF? receptor type II in cranial neural crest cells leads to craniofacial malformations, including cleft palate in mice (Tgfbr2(fl/fl);Wnt1-Cre mice). Here we have identified candidate target genes of TGF? signaling during palatal formation. These target genes were selected based on combining results from gene expression profiles of embryonic day 14.5 palates from Tgfbr2(fl/fl);Wnt1-Cre mice and previously identified cleft palate phenotypes in genetically engineered mouse models. We found that fibroblast growth factor 9 (Fgf9) and transcription factor pituitary homeobox 2 (Pitx2) expressions are significantly down-regulated in the palate of Tgfbr2(fl/fl);Wnt1-Cre mice, and Fgf9 and Pitx2 loss of function mutations result in cleft palate in mice. Pitx2 expression is down-regulated by siRNA knockdown of Fgf9, suggesting that Fgf9 is upstream of Pitx2. We detected decreased expression of both cyclins D1 and D3 in the palates of Tgfbr2(fl/fl);Wnt1-Cre mice, consistent with the defect in cell proliferation. Significantly, exogenous FGF9 restores expression of cyclins D1 and D3 in a Pitx2-dependent manner and rescues the cell proliferation defect in the palatal mesenchyme of Tgfbr2(fl/fl);Wnt1-Cre mice. Our study indicates that a TGF?-FGF9-PITX2 signaling cascade regulates cranial neural crest cell proliferation during palate formation.

SUBMITTER: Iwata J

PROVIDER: S-EPMC3268397 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Fibroblast growth factor 9 (FGF9)-pituitary homeobox 2 (PITX2) pathway mediates transforming growth factor β (TGFβ) signaling to regulate cell proliferation in palatal mesenchyme during mouse palatogenesis.

Iwata Jun-ichi J Tung Lily L Urata Mark M Hacia Joseph G JG Pelikan Richard R Suzuki Akiko A Ramenzoni Liza L Chaudhry Obaid O Parada Carolina C Sanchez-Lara Pedro A PA Chai Yang Y

The Journal of biological chemistry 20111128 4

Cleft palate represents one of the most common congenital birth defects. Transforming growth factor β (TGFβ) signaling plays crucial functions in regulating craniofacial development, and loss of TGFβ receptor type II in cranial neural crest cells leads to craniofacial malformations, including cleft palate in mice (Tgfbr2(fl/fl);Wnt1-Cre mice). Here we have identified candidate target genes of TGFβ signaling during palatal formation. These target genes were selected based on combining results fro ...[more]

PMID: 22123828

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Project description:During palatogenesis, the palatal shelves first grow vertically on either side of the tongue before changing their direction of growth to horizontal. The extracellular matrix (ECM) plays an important role in these dynamic changes in palatal shelf morphology. Tenascin-C (TNC) is an ECM glycoprotein that shows unique expression in the posterior part of the palatal shelf, but little is known about the regulation of TNC expression. Since transforming growth factor-beta-3 (TGF-?3) and sonic hedgehog (SHH) signaling are known to play important roles in palatogenesis, we investigated whether TGF-?3 and SHH are involved in the regulation of TNC expression in the developing palate. TGF-?3 increased the expression of TNC mRNA and protein in primary mouse embryonic palatal mesenchymal cells (MEPM) obtained from palatal mesenchyme dissected at embryonic day 13.5-14.0. Interestingly, immunohistochemistry experiments revealed that TNC expression was diminished in K14-cre;Tgfbr2 fl/fl mice that lack the TGF-? type II receptor in palatal epithelial cells and exhibit cleft soft palate, whereas TNC expression was maintained in Wnt1-cre;Tgfbr2 fl/fl mice that lack the TGF-? type II receptor in palatal mesenchymal cells and exhibit a complete cleft palate. SHH also increased the expression of TNC mRNA and protein in MEPM cells. However, although TGF-?3 up-regulated TNC mRNA and protein expression in O9-1 cells (a cranial neural crest cell line), SHH did not. Furthermore, TGF-? inhibited the expression of osteoblastic differentiation markers (osterix and alkaline phosphatase) and induced the expression of fibroblastic markers (fibronectin and periostin) in O9-1 cells, whereas SHH did not affect the expression of osteoblastic and fibroblastic markers in O9-1 cells. However, immunohistochemistry experiments showed that TNC expression was diminished in the posterior palatal shelves of Shh-/+ ;MFCS4 +/- mice, which have deficient SHH signaling in the posterior palatal epithelium. Taken together, our findings support the proposal that TGF-? and SHH signaling in palatal epithelium co-ordinate the expression of TNC in the posterior palatal mesenchyme through a paracrine mechanism. This signal cascade may work in the later stage of palatogenesis when cranial neural crest cells have differentiated into fibroblast-like cells. The spatiotemporal regulation of ECM-related proteins by TGF-? and SHH signaling may contribute not only to tissue construction but also to cell differentiation or determination along the anterior-posterior axis of the palatal shelves.

Project description:Dopamine and estradiol interact in the regulation of lactotroph cell proliferation and prolactin secretion. Ablation of the dopamine D2 receptor gene (Drd2(-/-)) in mice leads to a sexually dimorphic phenotype of hyperprolactinemia and pituitary hyperplasia, which is stronger in females. TGF-?1 is a known inhibitor of lactotroph proliferation. TGF-?1 is regulated by dopamine and estradiol, and it is usually down-regulated in prolactinoma experimental models. To understand the role of TGF-?1 in the gender-specific development of prolactinomas in Drd2(-/-) mice, we compared the expression of different components of the pituitary TGF-?1 system, including active cytokine content, latent TGF-?-binding protein isoforms, and possible local TGF-?1 activators, in males and females in this model. Furthermore, we evaluated the effects of dopamine and estradiol administration to elucidate their role in TGF-?1 system regulation. The expression of active TGF-?1, latent TGF-?-binding protein isoforms, and several putative TGF-?1 activators evaluated was higher in male than in female mouse pituitary glands. However, Drd2(-/-) female mice were more sensitive to the decrease in active TGF-?1 content, as reflected by the down-regulation of TGF-?1 target genes. Estrogen and dopamine caused differential regulation of several components of the TGF-?1 system. In particular, we found sex- and genotype- dependent regulation of active TGF-?1 content and a similar expression pattern for 2 of the putative TGF-?1 activators, thrombospondin-1 and kallikrein-1, suggesting that these proteins could mediate TGF-?1 activation elicited by dopamine and estradiol. Our results indicate that (1) the loss of dopaminergic tone affects the pituitary TGF-?1 system more strongly in females than in males, (2) males express higher levels of pituitary TGF-?1 system components including active cytokine, and (3) estradiol negatively controls most of the components of the system. Because TGF-?1 inhibits lactotroph proliferation, we propose that the higher levels of the TGF-?1 system in males could protect or delay the development of prolactinomas in Drd2(-/-) male mice.

Dataset Information

Fibroblast growth factor 9 (FGF9)-pituitary homeobox 2 (PITX2) pathway mediates transforming growth factor ? (TGF?) signaling to regulate cell proliferation in palatal mesenchyme during mouse palatogenesis.

Publications

Fibroblast growth factor 9 (FGF9)-pituitary homeobox 2 (PITX2) pathway mediates transforming growth factor β (TGFβ) signaling to regulate cell proliferation in palatal mesenchyme during mouse palatogenesis.

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